GEN News Highlights

Stress Gene Linked to Deadly Cardiac Events

Possessing a genetic variant for heightened stress sensitivity can be a source of stress all by itself. But wait, it’s worse—the same genetic variant is also linked to a 38% increased risk of heart attack or death in patients with heart disease.

The genetic variant is a single nucleotide polymorphism (rs6318) of the X-chromosome gene encoding the serotonin 2C receptor (5HTR2C). Ordinarily, this gene helps mediate stress-induced hypothalamic-pituitary-adrenal axis activation via stress-induced release of serotonin in the central nervous system. However, when this gene is present in altered form—that is, as the rs6318 variant—it causes a hyperactive reaction to stress.

In a study published last year, researchers reported that men with this genetic variant had twice as much cortisol in their blood when exposed to stress, compared to men without the genetic variant. Known as a “stress hormone,” cortisol is produced in the adrenal gland to support the body’s biological response when reacting to a situation that causes negative emotions.

The researchers responsible for this finding continued their work by investigating whether people carrying the rs6318 variant were at higher risk for cardiovascular disease. Using a large database of heart catheterization patients, the researchers ran genetic analyses of more than 6,100 white participants, two-thirds of whom were men, and one-third women. About 13% of this group had the genetic variation for the overactive stress response.

Patients who carried the genetic variation had the highest rates of heart attacks and deaths over the median follow-up time of six years. Even adjusting for age, obesity, smoking history, other illnesses and the severity of their heart disease, the genetic trait was associated with a 38% increased risk of heart attack and death.

These results were published December 18 in PLOS ONE, in an article entitled “A Functional Polymorphism in the 5HTR2C Gene Associated with Stress Responses Also Predicts Incident Cardiovascular Events.” The article’s authors, based at Duke University Medical Center, suggest that their study has potentially important implications for the development of targeted preventive interventions and treatments.

In their article, the authors highlighted potential interventions. For example, the authors cited a study that showed the benefits of cognitive behavioral stress management training. When such training was extended to women undergoing treatment for breast cancer, levels of anxiety and cortisol levels were reduced, and the reductions were maintained over a 12-month follow-up period. “A more direct clinical implication of the current findings,” added the authors, “is that persons carrying the 5HTR2C rs6318 Ser23C allele might benefit from treatment with an antagonist of the 5HTR2C receptor.”

“We’ve heard a lot about personalized medicine in cancer, but in cardiovascular disease we are not nearly as far along in finding the genetic variants that identify people at higher risk,” said senior author Redford B. Williams, Jr., M.D., director of the Behavioral Medicine Research Center at Duke University School of Medicine. “Here we have a paradigm for the move toward personalized medicine in cardiovascular disease.”

Upon learning that they carry the stress gene, individuals aware of the potentially dire implications may react with a surge of anxiety, at least initially. The stress gene, however, needn’t trigger a self-fulfilling prophecy. Instead of stressing over the implications of being vulnerable to stress, individuals may be relieved to find that they are candidates for targeted interventions.

“The exciting part to me this is that this genetic trait occurs in a significant proportion of people with heart disease,” said lead author Beverly H. Brummett, Ph.D., associate professor of psychiatry and behavioral sciences at Duke. “If we can replicate this [finding] and build on it, we may be able to find ways to reduce the cortisol reaction to stress—either through behavior modification or drug therapies—and reduce deaths from heart attack.”

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